Discovery and Optimization of a Novel Spiropyrrolidine Inhibitor of β-Secretase (BACE1) through Fragment-Based Drug Design
Discovery and Optimization of a Novel Spiropyrrolidine Inhibitor of β-Secretase (BACE1) through Fragment-Based Drug Design
复制标题
DOI：
10.1021/jm201715d
复制
发表时间：
2012-11-08
影响因子：
7.3
通讯作者：
Withka, Jane M.
中科院分区：
文献类型：
--
作者：
Efremov, Ivan V.;Vajdos, Felix F.;Withka, Jane M.
天冬氨酰蛋白酶 β 分泌酶 (BACE) 已被证明是 A β 肽蛋白水解形成的关键因素，A β 肽是阿尔茨海默病 (AD) 患者大脑斑块的主要成分，抑制这种酶已成为 AD 药物干预的主要策略。对辉瑞专有片段集合进行基于 X 射线的片段筛选，鉴定出了一种具有螺吡咯烷框架的新型 BACE 结合剂。尽管对 BACE 酶仅表现出微弱的抑制活性，但该小化合物已通过生物物理和基于 NMR 的方法验证为真正的 BACE 抑制剂。随后对先导化合物的优化，在很大程度上依赖于基于结构的药物设计和理化性质的计算预测，使效力提高了近 1000 倍，同时保持配体效率和预测良好渗透性和低 P-gp 责任的性质。
The aspartyl protease beta-secretase, or BACE, has been demonstrated to be a key factor in the proteolytic formation of A beta-peptide, a major component of plaques in the brains of Alzheimer's disease (AD) patients, and inhibition of this enzyme has emerged as a major strategy for pharmacologic intervention in AD. An X-ray-based fragment screen of Pfizer's proprietary fragment collection has resulted in the identification of a novel BACE binder featuring spiropyrrolidine framework. Although exhibiting only weak inhibitory activity against the BACE enzyme, the small compound was verified by biophysical and NMR-based methods as a bona fide BACE inhibitor. Subsequent optimization of the lead compound, relying heavily on structure-based drug design and computational prediction of physiochemical properties, resulted in a nearly 1000-fold improvement in potency while maintaining ligand efficiency and properties predictive of good permeability and low P-gp liability.